Hypoxia is a characteristic feature of glioblastoma, as well as many other malignant tumors, and is associated with poor patient prognosis. The hypoxic microenvironment drives tumor progression by triggering adaptive transcriptional responses, including the hypoxia-inducible factors (HIFs) and tumor suppressor Von Hillel Landau (VHL) that targets HIF2a for degradation by a mechanism that is not well understood. Despite the substantial demand for new therapeutics for glioblastomas, there are currently limited drugs on the market that target either VHL or HIF2. This technology reveals the cellular mechanism utilized by glioblastoma cells by identifying molecular regulators used in the hypoxic niche. As a result, this technology pinpoints a potential therapeutic target for the treatment of hypoxia-driven cancers.
The standard of care for treating gliomas is a combination of chemotherapy and radiation therapy. These treatment options often result in severe side effects for patients, which can decrease quality of life. Newer targeted therapies have focused on blocking angiogenesis and metabolism in cancer cells to curb cell proliferation; however, gliomas instead rely on a hypoxic niche of stem cells in order to proliferate. Targeting this pathway in cells is an attractive therapeutic option for reducing hypoxia-driven cancer stem cell growth.
This technology identifies kinases DYRK1A/B as targeting ID2 for degradation through phosphorylation, subsequently preventing it from inhibiting the VHL complex. As a result, HIF2a undergoes increased degradation, thus reducing the cancer cell’s ability to survive in a hypoxic environment. Therefore, DYRK1 is a potential therapeutic for treating hypoxic cancer stem cells. This technology also utilizes isolated prolyl hydroxylase (PHD) proteins as a therapeutic strategy, due to their effects on DYRK1 and their ability to provide hydroxylation sites that can be targeted separately from other oxygen-independent pathways. Successfully inhibiting cancer cell proliferation in this environment with this level of specificity can potentially offer treatment options to glioblastoma patients, as well as for those with other tumors associated with hypoxia.
This technology has been tested in vivo by overexpressing DYRK in a mouse model of human glioma, which inhibited tumor cell proliferation. Furthermore, deletion of ID2 in a mouse model of malignant glioma led to a decrease in HIF2.
Patent Issued (US 11,045,525)
IR CU16166, CU17182
Licensing Contact: Kristin Neuman
